ABSTRACT Obstructive sleep apnea (OSA) is a common disorder whose prevalence is increasing. Sleep apnea is a systemic disorder, with recurrent falls in oxygen (hypoxia) and reoxygenation (oxidative stress) affecting every tissue. Thus, sleep apnea is an independent risk factor for cardiovascular disease (heart attack and stroke), hypertension, cognitive impairment and dementia, and cancer. However, there are major individual differences, with some individuals even with severe OSA not developing any of these consequences. While it has been known for two decades that OSA aggregates in families, no convincing gene variants conferring risk have been identified in human studies. This suggests that a new approach is required. The study we propose introduces the following new approaches: a) it will be conducted in mice as a model system. Mice have proven to be a powerful model system to identify gene variants for human disease; we will use the recently described Diversity Outbred strategy that identifies quantitative trait loci of the order of three genes. This requires high throughput phenotyping of large numbers of genetically heterogeneous mice in combination with genotyping by a universal mouse SNP chip; b) we will study key endophenotypes that confer risk to OSA?tongue fat and ventilatory responses to hypoxia and hypercapnia. We will assess heritability of each of these traits and determine if tongue fat is a unique fat distribution; and c) we will assess the blood pressure response to cyclical intermittent hypoxia that simulates the pattern of deoxygenation/reoxygenation that occurs in patients with OSA. For all phenotypes assessed, functional assessment of genes identified will be performed. Thus, the study introduces an entirely novel approach to identifying gene variants and performing a functional assessment of genes for all phenotypes assessed. Large numbers of human samples with well phenotyped individuals are already in hand to translate findings from these mouse studies to humans, and in particular the phenotypes being assessed in these mouse studies are being assessed in a quantitative manner in the two human projects (Projects 01, 02). Sequencing of genes identified will be performed in the samples from the other projects in the Program Project Grant.